Sales of antibiotics without a prescription in pharmacies, 2017 and 2021, China

Abstract Objective To measure sales of antibiotics without a prescription in pharmacies in China in 2017 and 2021, before and during the coronavirus disease 2019 (COVID-19) pandemic, and determine the factors associated with such sales. Methods We conducted cross-sectional surveys using the simulated patient method in retail pharmacies in 13 provinces in eastern, central and western China in 2017 and 2021. At the pharmacies, the simulated patients (trained medical students) reported that they had mild respiratory tract symptoms and asked for treatment, using a three-stage process: (i) request some treatment; (ii) request antibiotics; (iii) request specific antibiotics. We used multivariable logistic regression analysis to determine factors associated with sale of antibiotics without a prescription. Findings Of the pharmacies visited in 2017, 83.6% (925/1106) sold antibiotics without a prescription; this figure was 78.3% (853/1090) in 2021 (P-value: 0.002). After excluding pharmacies prohibited from selling antibiotics because of COVID-19, this difference was not significant (83.6% versus 80.9%; 853/1054; P-value: 0.11). Factors significantly associated with selling antibiotics without a prescription in both 2017 and 2019 were: location in central and western China compared with eastern China; being in a township or village compared with in a city; and presence of a counter where antibiotics were dispensed. Conclusion Although laws became stricter between 2017 and 2021, antibiotic sales without a prescription were still common in pharmacies across China. Existing regulations need to be more strictly enforced, and pharmacy staff and the public should be made more aware of the risks of antibiotic misuse and dangers of antimicrobial resistance.


Introduction
Antimicrobial resistance is one of the most serious threats to the health of the world's population. 1,2 In 2019, antimicrobial resistance was associated with 4.95 million deaths globally. 3 Estimates suggest that antimicrobial resistance could lead to about 10 million deaths a year by 2050 unless urgent measures are taken. 2 Misuse of antibiotics in agriculture and health care is the primary driver of antimicrobial resistance. 4,5 In health care, antimicrobial stewardship programmes targeting doctors' prescribing have been introduced in many countries with some success. 6 For instance, in China, a national campaign on the rational use of antibiotics was conducted in hospitals, which resulted in a 10% decrease in prescriptions with antibiotics in both inpatient and outpatient settings. 7 However, globally, nearly half of antibiotics were purchased without prescription from retail pharmacies. [8][9][10][11] China is one of the world's largest consumers and producers of antibiotics, and one of the drivers of antimicrobial resistance globally. 12 In a national survey in 2020, the resistance rates of some bacteria were high nationwide. For example, erythromycin resistance was reported in 96.0% (73 355/76 412) of strains of Streptococcus pneumoniae. 13 Apart from some topical antibiotics, such as chlortetracycline and erythromycin which are over-the-counter medicines, the law states that most antibiotics need to be purchased on prescription in China. Recent studies have shown that most retail pharmacies in China sold antibiotics without a prescription to simulated patients describing mild symptoms. [14][15][16][17][18] The main types of antibiotics offered were penicillins (36.0%; 333/925), cephalosporins (29.6%; 274/925) and macrolides (27.0%; 250/925). 15 Concerns about the growing problem of sales of antibiotics without a prescription have led to action by the Chinese government (see online repository). 19 In 2003, policies on antimicrobial resistance were issued, including a ban on the sale of antibiotics without a prescription. 20 In 2011, the health ministry established a task force on antibiotic stewardship in hospitals, which resulted in small reductions in antibiotic prescribing, especially in tertiary hospital settings. 21 In 2012, the twelfth five-year plan on drug safety proposed that a licensed pharmacist guide the rational use of medicines and monitor drug use, including addressing the inappropriate use of antibiotics. 22 In 2016, at the G20 summit, China affirmed the importance of tackling antimicrobial resistance. The Chinese government issued the National Action Plan with the goal of achieving all sales of antibiotics with a prescription in pharmacies by 2020. 23 From 2011 to 2017, a decrease in sales of antibiotics without a prescription was observed in China, especially in Shanxi province where multiple initiatives had been taken. 14 In 2020, further controls were announced, including that retail pharmacies selling antibiotics without prescriptions would be penalized more severely, 24 with a steep increase in fines from about 1000 renminbi (¥), equivalent to 140 United States dollars (US$), 25 to ¥ 30 000 (US$ 4215). 24 This measure mirrors policies in other countries, where fines for selling antibiotics without prescriptions have been introduced, and where effectiveness depends on the degree of enforcement and the size of the fine. [26][27][28][29] Objective To measure sales of antibiotics without a prescription in pharmacies in China in 2017 and 2021, before and during the coronavirus disease 2019 (COVID-19) pandemic, and determine the factors associated with such sales. Methods We conducted cross-sectional surveys using the simulated patient method in retail pharmacies in 13 provinces in eastern, central and western China in 2017 and 2021. At the pharmacies, the simulated patients (trained medical students) reported that they had mild respiratory tract symptoms and asked for treatment, using a three-stage process: (i) request some treatment; (ii) request antibiotics; (iii) request specific antibiotics. We used multivariable logistic regression analysis to determine factors associated with sale of antibiotics without a prescription. Findings Of the pharmacies visited in 2017, 83.6% (925/1106) sold antibiotics without a prescription; this figure was 78.3% (853/1090) in 2021 (P-value: 0.002). After excluding pharmacies prohibited from selling antibiotics because of COVID-19, this difference was not significant (83.6% versus 80.9%; 853/1054; P-value: 0.11). Factors significantly associated with selling antibiotics without a prescription in both 2017 and 2019 were: location in central and western China compared with eastern China; being in a township or village compared with in a city; and presence of a counter where antibiotics were dispensed. Conclusion Although laws became stricter between 2017 and 2021, antibiotic sales without a prescription were still common in pharmacies across China. Existing regulations need to be more strictly enforced, and pharmacy staff and the public should be made more aware of the risks of antibiotic misuse and dangers of antimicrobial resistance.

Research
Antibiotic sales without prescriptions, China Jie Chen et al.
Efforts to tackle antimicrobial resistance have been complicated by the coronavirus disease 2019 (COVID- 19) pandemic. During the first wave of the pandemic in 2020, estimates suggest that, globally, about half of hospitalized patients with COVID-19 died of bacterial or fungal infections. 27 Antibiotics became widely used as part of the routine treatment for COVID-19, 28 although limited evidence was available of their effect on health outcomes. 29 Reports from 2022, much later in the course of the pandemic, indicated that only 2.5% (25/989) to 5.1% (21/408) of hospitalized patients with COVID-19 were co-infected with bacteria. 30 In some areas of China, during local COVID-19 outbreaks, drug sales for respiratory symptoms were temporarily banned (usually for 1-2 months) in retail pharmacies. These medicines included cough suppressants, in addition to antibiotics. 31,32 The reason for this ban was because self-medication was thought to delay the diagnosis of COVID-19, thus increasing the risk of its spread in the population. 20 Several studies exploring the sale of antibiotics without a prescription in China were conducted before the outbreak of COVID-19. 14, [16][17][18] In this study, we aimed to: (i) compare the prevalence of antibiotic sales without a prescription in 2017 and 2021, before and after the new stricter regulations introduced during COVID-19 in China; and (ii) explore the characteristics of the pharmacies where antibiotics were sold without a prescription, as well as the quality of service during antibiotic sales.

Methods
We used the same method for both the 2017 and 2021 surveys, that is, a crosssectional study using the simulated patient method. We conducted the surveys in the same 13 provinces in the three geographic regions of mainland China (see online repository). 19 We used a multistage sampling process in both surveys. We used purposive sampling to select four to five provinces each in the eastern, central and western regions of China to broadly represent socioeconomic status. In each province, we selected the capital city, one small city and one county. The small cities and counties were different in the two surveys. We selected at least 80 pharmacies per province and all pharmacies were within 10 km of the simulated patient's home.

Categories of pharmacies
To ensure a broad representation of types of pharmacy, we purposively selected pharmacies within three categories. We used Google or Baidu maps for location information. 15

Administrative level
We categorized pharmacies according to administrative level: city, county, or township and village. Cities were urban areas, townships and villages were rural areas, and counties were rural regions with urban characteristics. A previous study assumed that it may be harder to obtain antibiotics without a prescription in urban areas where policies on sales of antibiotics are more likely to be enforced than in than rural areas. 15

Distance from a hospital
We categorized pharmacies as being within 2 km of a hospital or more than 2 km of a hospital. Previous research showed that pharmacies near a hospital may be less likely to offer antibiotics without a prescription because prescriptions are more readily available at the hospital. 15

Type of pharmacy
We categorized pharmacies as independent or part of a chain of pharmacies. We assumed that independent pharmacies were less regulated and so may be more likely to sell antibiotics without a prescription. 15

Procedures
We used the simulated patient method in both surveys. We recruited 100 undergraduate medical students and trained them to act as simulated patients (49 students in 2017 and 51 students in 2021). The students were from Zhejiang University, Xiamen University, Xiangya School of Medicine and Sun Yat-sen University.
We conducted the surveys from July to September in 2017 and 2021. The medical students (simulated patients) went to the pharmacies selected and followed the three stages of the protocol (Fig. 1). We instructed students to describe the symptoms of a mild upper respiratory tract infection, to deny any symptoms of fever, not to display any visible symptoms and not to insist on being given antibiotics. When the pharmacy refused to sell antibiotics, the specific reason was recorded, including: a prescription was required; antibiotics were not indicated; no antibiotics were in stock; antibiotic sales were banned; or any other reasons.

Analysis
We used descriptive statistics with frequencies and 95% confidence intervals (CIs). We used the χ 2 test to compare the characteristics of pharmacies. We used multivariable logistic regression analyses to compare the pharmacies that sold antibiotics without prescription with pharmacies that did not. We used R version 4.2.1 (R Foundation, Vienna, Austria) for all statistical analyses.

Ethical approval
We obtained ethical approval for the study from the Institutional Ethical Clearance Committee, Zhejiang University School of Public Health (approval numbers ZGL201706-5 and ZGL202107-1). Because of the nature of the simulated patient method, the committee waived the need for consent of the pharmacies. The aim of the study was not to expose pharmacy violations, but to anonymously report the prevalence of the sale of antibiotics without a prescription.
Most of the simulated patients were able to buy antibiotics when they asked directly for antibiotics at stage 2, 52.1% (576/1106) in 2017 and 52.4%  Observations outside the pharmacy: record distance from the hospital and whether it is an independent pharmacy or part of a chain. Turn on the recording device.
Observations inside the pharmacy: record size, availability of licensed pharmacists, prescription sales signs and antibiotic counters.
Start query: "my throat is a little uncomfortable and I also have a slight headache (deny fever) since I got up in the morning." Leave without any drugs: "sorry, I forgot my wallet at home." Outside the pharmacy: record the process on the telephone immediately after leaving the pharmacy.    Table 5).

Discussion
This study evaluated sales of antibiotics without a prescription in retail pharmacies in mainland China in 2017 and 2021, before and during COVID-19. In both surveys, healthy young adults with no actual symptoms were easily able to buy antibiotics without a prescription at a retail pharmacy. Overall, sales of an-

2021
Note: Stage 1: asked for medicine for a sore throat and headache; stage 2: asked for an antibiotic; stage 3: asked for amoxicillin or cephalosporin.
Antibiotic sales without prescriptions, China Jie Chen et al. tibiotics without a prescription slightly but significantly declined, regardless of the type, size, or other characteristics of the pharmacies. However, after excluding cases where antibiotics could not be purchased because of COVID-19, mainly in Shanxi, Anhui and Jiangsu, such sales did not decrease significantly between 2017 and 2021, even though stricter policies and regulations on antimicrobial resistance had been in place since 2020. 24,33 In recent studies in China on sales of antibiotics without a prescription, these sales ranged from 70.1% (1690/2411) to 88.4% (130/147). 14,17,18 Antibiotics without a prescription were found to be more easily obtained in western China (OR: 2.35; 95% CI: 1.27-4.34) 14,16 and in rural areas (OR: 2.17; 95% CI: 1.32-3.57), 14,34 which is in line with our results. Globally, studies on sales of antibiotics without a prescription have been done in many settings, especially in low-and middle-income countries. 8,35 A systematic review and meta-analysis of studies in 24 countries where antibiotics were classed as prescription-only medicines, showed that the overall proportion of community pharmacies providing antibiotics without a prescription was 62% (95% CI: 53-72) which increased to 78% (95% CI: 59-97) if the patient requested them. 8 A similar study in sub-Saharan African countries showed that 69% (95% CI: 58-80) of requests for antibiotics without a prescription in community pharmacies resulted in antibiotics being given. 35 The sale of antibiotics may also have been influenced by COVID-19 regulations. Our survey in 2021 was conducted when COVID-19 had been brought under control after the first phase of the pandemic in China, when only small sporadic outbreaks were occurring. In 2021, most pharmacies visited asked clients to take their temperature and register individual information to assist with identification of suspected CO-VID-19 cases. In places with COVID-19 cases, strict lockdowns and movement restrictions were imposed. In some of these areas, people were able to leave their homes to buy medicines for upper respiratory tract symptoms (sometimes including antibiotics) in a pharmacy, thus avoiding the compulsory nucleic acid test in hospital. 36,37 This situation may have increased the sale of antibiotics without a prescription in retail pharmacies. Such sales were mainly driven  by profit, 38 because of the need to make up for lost income during the pandemic. Our two surveys identified some common issues. First, they illustrate the importance of the demand side in illegal antibiotic sales. Most simulated patients in our surveys were given antibiotics without a prescription when they asked directly for an antibiotic at stage 2. In 2021, the simulated patients had significantly less access to antibiotics at stage 1 and greater access at stage 3 compared with in 2017. Pharmacists would sell at the specific request of the patient. This finding may be partly explained by the results of a nationwide community survey in China, which showed that more than 60% of the public believed that antibiotics could treat viral diseases. 38 National education campaigns and programmes are needed to raise public awareness of the risks of antibiotic misuse.
Second, the quantity and quality of pharmacists should be strengthened. Trained pharmacists are easily approachable professionals 39 and can help patients choose suitable treatments. 14,40-42 However, our study showed that more than half of pharmacies had no licensed pharmacist on duty in 2017, a number that decreased to about one third in 2021, even though by law a licensed pharmacist should be present for the sale of prescription drugs. In 2021, the total number of retail pharmacies in China was 586 530, 43 but there was a shortage of licensed pharmacists. As for the quality of services, most of the pharmacists did not ask patients if they had seen a doctor, whether they had a prescription, or whether they had a history of drug allergy. About a third of the pharmacies did not enquire about the patient's condition, nor did they of-fer any advice about other medication, with no changes from 2017 to 2021. To improve the quality of services, pharmacists need to be educated in basic prescribing practice. In addition, local health bureaus should take responsibility for monitoring pharmacists' prescribing behaviour and improving pharmacy management.
A strength of our study was that the surveys were conducted with a standard procedure and on a large sample across China. Furthermore, we used the simulated patient method which is regarded as the gold standard for this type of research. Our study also had some limitations. First, we only included about 80 pharmacies per province. However, the pharmacies were purposively sampled to include a range of different categories of pharmacy. Second, we only conducted the study in 13 out of 31 provinces in mainland China and used just one specific disease description (mild upper respiratory tract infection); thus, generalization of the results should be made with caution.
Given the ease with which the public can obtain antibiotics without a prescription in pharmacies across China, despite the fact that legislation banning this practice has been in place for nearly 20 years, measures to strengthen good prescribing practice are needed. First, enforcement of the existing legislation is needed. This action could be the responsibility of local health bureaus, as noted above. Second, in parallel with this enforcement, a higher level of fines should be imposed for pharmacies that break the law. Evidence from other countries shows that fines can be an effective deterrent and result in compliance with legislation and regulations. For example, in Saudi Arabia, sales of antibiotics with-out a prescription decreased after fines were increased and regulations were enforced; 44 however, in Viet Nam, increased fines did not significantly affect such sales. 45 A system of standardized prescriptions could be developed with traceable authentication, for example, a quick response (QR) code. New technology such as tracking and tracing systems could also be applied. 46,47 Third, a single regulation measure may not be sufficient, as a study in South Africa showed that a combination of regulations, including a ban on sales of antibiotics without a prescription, supervision of prescribing by licensed pharmacists, and sets of ethical and professional codes were necessary to change behaviour. 48 Fourth, educational programmes for pharmacists, in parallel with education campaigns for the general public, need to be conducted. Finally, the authorities could also disclose the names of pharmacies selling antibiotics illegally, since social norms can help with behaviour modifications. 26,45,49 To conclude, despite efforts by the government to tackle illegal sales of antibiotics in pharmacies, little has changed over the past 4 years.   После исключения аптек, которым запрещалось продавать антибиотики из-за COVID-19, эта разница перестала быть существенной (83,6% против 80,9%; 853/1054; P-значение: 0,11). К числу факторов, в значительной степени связанных с продажей антибиотиков без рецепта в 2017 и 2019 гг., относятся: расположение в регионах Центрального и Западного Китая по сравнению с Восточным Китаем; проживание в поселке или деревне по сравнению с городом; наличие прилавка, где отпускаются антибиотики.